Compressed tablet containing cannabidiol, method for its manufacture and use of such tablet in oral treatment of psychosis or anxiety disorders

ABSTRACT

The invention further provides a method for the manufacture of the compressed tablets.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.15/032,905, filed Apr. 28, 2016, which is the U.S. National Phase ofInternational Patent Application No. PCT/NL2014/050745, filed Oct. 29,2014, published on May 7, 2015 as WO 2015/065179 A1, which claimspriority to European Patent Application No. 13190587.9, filed Oct. 29,2013. The contents of these applications are herein incorporated byreference in their entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compressed tablets containing agranulate comprising lactose particles, cannabidiol and a sucrose fattyacid mono-ester. These compressed tablets are particularly suited forperoral administration and can be conveniently used in peroral treatmentof psychosis or anxiety disorders. The invention also provides a methodfor the manufacture of the compressed tablets.

BACKGROUND OF THE INVENTION

The use of antipsychotic drugs for the treatment of schizophrenia-likesymptoms is often associated with adverse side effects such as motordisturbances, weight gain and sexual dysfunction. Hence, there is acontinuous need for alternative well-tolerated antipsychotic drugs.

It has been known since long that different components of the plantCannabis sativa (cannabis) have pharmacological activity. Cannabiscontains various cannabinoids, two of which have almost opposingactions. Δ9-Tetrahydrocannabinol (THC), which is the most abundantcannabinoid in smoked cannabis, is known to be a psychotomimeticcomponent. In contrast, cannabidiol (CBD), which is another majorcannabinoid found in some strains of cannabis, has been found to haveantipsychotic properties.

The antipsychotic properties of CBD have been investigated. Publicationsdescribing studies in which schizophrenic patients were treated with CBDindicate that CBD is a well-tolerated alternative drug for the treatmentof for example schizophrenia.

CBD is a lipophilic substance that is not soluble in water. It issoluble in ethanol (36 mg/ml) and dimethylsulfoxide DMSO (60 mg/ml). CBDhas a melting point of about 66° C.

Bioavailability of pharmaceutical substances taken perorally, first ofall, depends on the extent to which the pharmaceutically activesubstance is absorbed from the intestinal environment across theintestinal mucosa. Lipophilic pharmaceutical substances are generallypoorly absorbed from the intestinal environment, inter alia because oftheir poor solubility and/or dispersibility in water.

Bioavailability of a pharmaceutical substance taken perorallyfurthermore depends on the susceptibility of the substance to theso-called first pass effect. Substances absorbed from the intestine,before being distributed throughout the body, have to pass the liverfirst where they may be metabolized immediately. CBD is generallyassumed to be rather susceptible to first-pass liver metabolization.

Oral bioavailability of CBD is low and unpredictable (S. Zhornitsky, S.Potvin, Pharmaceuticals (2012) 5, 529-552). In addition, CBD is anunstable drug (A. J. Poortman, H. Huizer, Forensic Science International(1999) 101, 1-8).

Therapeutic applications of CBD have been described in severalpublications.

F. M. Leweke et al. (Transl. Psychiatry (2012) 2, e94) describe thetreatment of humans of age between 18 and 50 years old suffering fromacute paranoid schizophrenia by daily administering 200 to 800 mg CBD ora similar dose of the potent antipsychotic drug amisulpride.

A. W. Zuardi et al. (Braz. J. Med. Biol. Res. (2006) 39, 421-429 andJournal of Psychopharmacology (2006) 20(5), 683-686) describe a casestudy in which a schizophrenic patient received high doses of CBD(dissolved in oil) up to 1500 mg/day for 4 weeks and showed significantimprovement during CBD treatment while a worsening was observed when theadministration was interrupted. In another case study, a patient with adiagnosis of schizophrenia was administered doses of CBD, starting with40 mg/day for 5 days, with the dose being doubled every 5 days up to1280 mg/day during a period of about 4 weeks. A trend for symptomimprovement was observed at a dose of 1280 mg/day.

US 2011/038958 relates to a method for treatment or prevention ofpsychosis or a psychotic disorder. The method of treatment comprisesadministering to a patient a therapeutically effective amount oftetrahydrocannabivarin (THCV) and/or CBD. US 2011/038958 describes anexperiment in which mice received once daily oral doses of 0.3 and 3mg/kg CBD in combination with pure THCV.

WO 2008/033024 describes dosage units for sublingual, buccal or oraladministration of water-insoluble pharmaceutically active substances.CBD is mentioned as an example of water-insoluble pharmaceuticallyactive substances. Example 1 describes the preparation of a monophasicmicrogranulate comprising the cannabinoid Δ-9-tetrahydrocannabinol, andsucrose monolaurate in a weight ratio of 1:15 using a dry granulationprocess. Example 3 of this patent application describes the manufactureof a tabletting powder for direct compression using 5 g of themicrogranulate obtained from Example 1 and 17 g of other componentsincluding 5 g of lactose and the compression to 7 mm tablets with atotal weight of 60 mg. Example 6 describes the preparation of tabletscontaining 61 mg of a microgranulate, 180 mg lactose and 10 mg of otherexcipients, said microgranulate being composed ofΔ-9-tetrahydrocannabinol (THC), sucrose monolaurate and xylitol. Themicrogranulate was prepared by successively dispersing sucrosemonolaurate and xylitol into molten xylitol, followed by cooling andgrinding.

WO 02/064109 describes a pharmaceutical formulation for use inadministration of a lipophilic medicament via a mucosal surface, whichformulation comprises at least one lipophilic medicament and at leastone self emulsifying agent. Also described are pharmaceuticalformulations in the form of a gel or a compressed tablet foradministration of a lipophilic medicament via the sublingual and/orbuccal mucosa. Among the lipophilic medicaments mentioned in WO02/064109 A2 are THC and mixtures of THC and CBD. The pharmaceuticalformulations are intended for the treatment of a variety of diseasesamong which are multiple sclerosis, spinal cord injury, peripheralneuropathy and other neurogenic pain. Example 6 of the patentapplication describes the preparation of a tablet for buccal orsublingual administration by dissolving glyceryl monostearate,polysorbate 80, ascorbyl palmitate and α-tocopherol and THC in alcohol,spraying the alcoholic solution onto a powder mix consisting of lactoseand soluble starch, evaporating the alcohol, dusting the resultinggranulate with talc and compressing to a target tablet weight of 101 mg.

WO 2009/087351 describes the use of one or more phyto-cannabinoids,including CBD, with one or more anti-psychotic medicaments in themanufacture of a pharmaceutical formulation for use in the prevention ortreatment of psychosis or a psychotic disorder, wherein the one or morephyto-cannabinoids are administered separately, sequentially orsimultaneously to the one or more anti-psychotic medicaments.

WO 2012/033478 describes an oral dosage form of cannabinoids, amongwhich CBD, in a self-emulsifying system operable to avoid hepatic firstpass metabolism, said oral dosage form comprising:

-   -   1-90 wt. % of a pharmacologically active form of cannabinoids;    -   15-85 wt. % of one or more triglycerides;    -   15-85 wt. % of one or more mixed glycerides; and    -   5-90 wt. % of a surfactant which promotes self-emulsification.

It is an object of the present invention to provide a dosage unit forperoral administration of CBD that combines high and predictablebioavailability with excellent stability. It is a further object of theinvention to provide dosage units for peroral administration of CBD thatcan conveniently be used in the treatment of psychosis disorders oranxiety disorders.

SUMMARY OF THE INVENTION

The inventors have developed a compressed tablet for peroral deliverythat meets these objectives. The tablet according to the presentinvention has a tablet weight of 60-1200 mg and is composed of: 50-95wt. % of a CBD-containing granulate, 5-50 wt. % of lactose and 0-30 wt.% of other tablet excipients. The granulate contains 2-15 wt. % of CBD,2-30 wt. % of sucrose fatty acid mono-ester, 30-96 wt. % of lactose and0-25 wt. % of other granulate excipients.

The oral bioavailability of the CBD in the tablets of the presentinvention is high as well as predictable. Furthermore, the compressedtablets are very stable in that CBD degradation during storage underambient conditions is minimal. The tablets according to the inventioncan conveniently be used in the treatment of psychosis disorders oranxiety disorders at daily doses in a total amount that is equivalent to5-1000 mg of CBD.

The invention further relates to a method of manufacturing a compressedtablet according to the present invention, said method comprising thesteps of:

-   -   providing a lactose powder having a mass weighted average        diameter of 32-250 μm;    -   combining the lactose powder with a granulation fluid to produce        a granulate, said granulation fluid comprising a solution of        CBD, sucrose fatty acid monoester, antioxidant and optionally        further granulate excipients in organic solvent;    -   removing the organic solvent by evaporation to produce a        granulate;    -   mixing the granulate with lactose and optionally further tablet        excipients to produce a tablet mixture; and    -   compressing the tablet mixture into a tablet.

Definitions

The term ‘compressed tablet’ as used herein refers to a mixture ofactive substances and excipients, pressed or compacted from a powderform into the solid pharmaceutical dosage form.

The term ‘granulate’ as used herein refers to a particulate materialthat consists of discrete particles, referred to as granules.

The term ‘granule’ refers to a particle that is composed of two or moresub-particles that are held together by physical forces, e.g. by abinding agent.

The term ‘granulation’ as used herein refers to a process that convertsa powder into a granulate. Wet granulation is a granulation method thatemploys a liquid to convert a powder into a granulate. The fluid isusually sprayed onto the powder while the powder is kept in motion. Thefluid acts as a binding agent that ‘glues’ together the powderparticles, thereby forming granules. This fluid is also referred toherein as ‘granulation fluid’. It typically contains a solvent which issufficiently volatile for removal by drying and that is non-toxic.

The term ‘oral’ or ‘peroral’ as used herein, unless indicated otherwise,refers to a mode of administration that involves ingestion of the dosageunit.

The term ‘mass weighted average diameter’ as used herein refers to theaverage diameter of particulate matter wherein the contribution of thediameter of a single particle to the average is proportional to the massof that single particle. The mass weighted average diameter of a powderor a granulate may suitably be measured by analytical sieve analysis.

The term ‘volume weighted average diameter’ as used herein refers anaverage particle diameter wherein the contribution of the diameter of asingle particle to the average is proportional to the volume of thatsingle particle. The relative volume-contribution of a single particleis usually assumed to be proportional to its (diameter)³.

The term ‘solid dispersion’ refers to compositions containing a drugdispersed or dissolved within a solid carrier matrix. Different types ofsolid dispersions can be distinguished on the basis of the physical formof the drug and the carrier. The drug is either suspended in the carrieras phase-separated crystalline or amorphous particles, or it exists as ahomogeneous molecular mixture of (amorphous) drug and carrier. Thecarrier can exist in amorphous or crystalline form. More information onsolid dispersions can be found in Williams et al., Strategies to AddressLow Drug Solubility in Discovery and Development, PharmacologicalReviews (2013) 65, 416-445.

The term ‘psychosis disorders’ as used herein refers to a disorder thatis accompanied by psychosis or psychotic symptoms.

The term ‘psychosis’ as used herein refers to a mental illness typicallycharacterized by radical changes in personality, impaired functioning,and a distorted or nonexistent sense of objective reality. Patientssuffering from psychosis have impaired reality testing; that is, theyare unable to distinguish personal subjective experience from thereality of the external world. They experience hallucinations and/ordelusions that they believe are real, and may behave and communicate inan inappropriate and incoherent fashion. Psychosis may appear as asymptom of a number of mental disorders, including mood and personalitydisorders. It is also the defining feature of schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, and the psychotic disorders (i.e., brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition, and substance-induced psychotic disorder).

The term ‘anxiety disorders’ as used herein refers to mental disordersin which anxiety and avoidance behavior predominate. Examples of suchdisorders include phobias (including agoraphobia), panic disorder,obsessive-compulsive disorder, posttraumatic stress disorder, acutestress disorder, generalized anxiety disorder, and substance-inducedanxiety disorder.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention relates to a compressed tablet having atablet weight of 60-1200 mg, said tablet being composed of 50-95 wt. %of a granulate, 5-50 wt. % of lactose and 0-30 wt. % of other tabletexcipients, wherein the granulate contains 2-15 wt. % of CBD, 2-30 wt. %of sucrose fatty acid mono-ester, 30-96 wt. % of lactose and 0-25 wt. %of other granulate excipients.

The compressed tablet of the present invention is composed of (preparedfrom) at least two particulate components, i.e. granulate, lactose andoptionally one or more excipients. Unless indicated otherwise thelactose concentrations mentioned herein refer to either the lactose thattogether with the granulate represents the bulk of the compressed tabletor the lactose that is contained within the granulate.

The weight of the compressed tablet preferably is within the range of100-1000 mg, more preferably in the range of 200-800 mg and mostpreferably in the range of 250-500 mg.

The amount of CBD contained in the compressed tablet preferably lieswithin the range of 2-100 mg, more preferably in the range of 5-90 mgand most preferably in the range of 10-80 mg.

The CBD-containing granulate typically represents at least 55 wt. %,more preferably at least 58 wt. % and most preferably at least 60 wt. %of the tablet. Preferably, said granulate represents not more than 90wt. %, especially not more than 85 wt. % and most preferably not morethan 80 wt. % of the tablet.

Lactose, other than the lactose contained in the CBD-containinggranulate, typically represents of at least 10 wt. %, more preferably ofat least 15 wt. % and most preferably of at least 20 wt. % of thetablet. Preferably, said lactose represents not more than 46 wt. %, morepreferably not more than 43 wt. % and most preferably not more than 40wt. % of the tablet.

The optional other tablet excipients are typically contained in thetablet in a concentration of not more than 25 wt. %, more preferably ina concentration of not more than 22 wt. % and most preferably in aconcentration of not more than 20 wt. %.

CBD is preferably contained in the granulate in a concentration of atleast 4 wt. %, especially of at least 5 wt. %.

Sucrose fatty acid mono-ester typically represent at least 5 wt. %, morepreferably at least 8 wt/% and most preferably at least 10 wt. % of thegranulate. Preferably the concentration of sucrose fatty acid mono-esterin the granulate does not exceed 27 wt. %, most preferably it does notexceed 25 wt. %.

Lactose is typically contained in the CBD-containing granulate in aconcentration of at least 45 wt. %, more preferably of at least 55 wt. %and most preferably of at least 60 wt. %. The lactose content of thegranulate preferably does not exceed 90 wt. %. More preferably, thelactose content of the granulate does not exceed 85 wt. %, even morepreferably it does not exceed 80 wt. %. Most preferably, said lactosecontent does not exceed 78 wt. %.

The optional other granulate excipients are typically contained in thegranulate in a concentration of not more than 22 wt. %, most preferablyin a concentration of not more than 20 wt. %. The term ‘granulateexcipients’ as used in the context of the present invention is not to beconstrued narrowly. Non-limiting examples of excipients that canconveniently be used in the granulate are preservatives, fats, waxes,and further pharmaceutically active substances, such as furthercannabinoids or analgesic drugs.

In an embodiment of the invention, a compressed tablet is provided asdefined herein, with the proviso that it is not a compressed tabletcomprising 75 wt % of a granulate, 23.8 wt. % of lactose, 1 wt % ofmagnesium stearate and 0.2 wt % of silicon dioxide, wherein thegranulate contains 8.0 wt. % of CBD, 16.0 wt. % of sucrose monolaurate,75.2 wt. % of lactose and 0.8 wt. % of ascorbic acid.

In a preferred embodiment, the granulate is composed of granules, saidgranules comprising lactose particles that are held together by a soliddispersion containing the CBD, sucrose fatty acid mono-ester andoptionally other granulate excipients.

The solid dispersion comprising CBD and sucrose fatty acid mono-ester isclearly distinguishable from the lactose particles and acts as a ‘glue’that holds together the lactose particles within the granules that makeup the granulate.

In an even more preferred embodiment, the granulate is composed ofgranules, said granules comprising lactose particles that are heldtogether by a solid dispersion, wherein the solid dispersion contains adispersed phase comprising CBD. Preferably, said dispersed phasecomprising CBD has a volume weighted average diameter between 2 nm and 1μm, more preferably of 2-500 nm, most preferably of 2-300 nm. The personskilled in the art is familiar with suitable techniques for determiningthe volume weighted average diameter of the dispersed phase containingCBD. Transmission electron microscopy is an example of a analyticaltechnique that can be used to determine the volume weighted averagediameter of the dispersed phase of the solid dispersion.

In a preferred embodiment, the granules constituting the granulate has amass weighted average diameter of 50-1000 μm, more preferably of 90-500μm and most preferably of 160-355 μm.

In a preferred embodiment the lactose constituting the lactose particleswithin the granulate is anhydrous lactose (β-lactose) or α-lactosemonohydrate. Anhydrous lactose is substantially free of (crystal) water.α-lactose monohydrate is lactose in which the lactose molecule isassociated with 1 molecule of water. The water is incorporated in thecrystal lattice and forms an integral part of it. Most preferably, thelactose contained in the granules is α-lactose monohydrate.

In a preferred embodiment, 70-100 wt. % of the lactose within thegranulate consists of α-lactose monohydrate, more preferably 75-100 wt.%, even more preferably 80-100 wt. %.

In a preferred embodiment, 90-100 wt. % of the lactose contained withinthe granulate consists of crystalline lactose, more preferably 95-100wt. %, even more preferably 98-100 wt. %.

In a preferred embodiment, the lactose within the granulate is aspray-dried lactose. Preferably the lactose used for producing thegranulate is obtainable by spray-drying a suspension of fine milledα-lactose monohydrate crystals in a solution of lactose. As is known bythose of average skill, lactose produced via spray-drying ismorphologically distinguishable from other lactose materials in that theparticles are spherical or substantially spherical, which provedadvantageous in the production of the granulate.

The CBD-containing granulate preferably contains 0.2-1.5 wt. %, morepreferably 0.4-1.2 wt % of antioxidant. The inventors have found thatthe inclusion of antioxidant significantly improves the stability of theCBD within the tablet.

In a preferred embodiment of the invention, the ratio of antioxidant toCBD (w/w) is within the range of 1:40-1:3, more preferably of 1:20-1:5,and most preferably of 1:15-1:7.5.

Non-limiting examples of antioxidants that can be employed in thegranulate include α-tocopherol (vitamin E), ascorbic acid (vitamin C),esters of ascorbic acid, vitamin A, flavanoids, polyphenols, butylatedhydroxy anisole, carotenes, ubiquinol (coenzyme Q10), and combinationsthereof. In a preferred embodiment the antioxidant is selected fromascorbic acid, esters of ascorbic acid and combinations thereof.Examples of esters of ascorbic acid that may be employed includefat-soluble esters of ascorbic acid with long-chain fatty acids (e.g.ascorbyl palmitate or ascorbyl stearate). Most preferably, theantioxidant employed is ascorbic acid.

As explained herein before THC is known to be a psychotomimeticcomponent. This means that THC may produce effects that resemble or areidentical with psychotic symptoms such as hallucinations or paranoiddelusions. The presence of THC in the compressed tablets according tothe invention can therefore counteract the intended antipsychoticproperties of the CBD and its concentration in the compressed tabletsaccording to the invention is therefore preferably kept low. Hence, in apreferred embodiment, the compressed tablet contains 0-5% THC by weightof CBD. In an even more preferred embodiment, the compressed tabletcontains 0-2% THC by weight of CBD. In a most preferred embodiment, thecompressed tablet contains less than 0.5% THC by weight of CBD.

Sucrose fatty acid mono-esters are amphiphilic compounds, i.e. theycomprise a hydrophilic and a lipophilic part. The balance between theirhydrophilicity and lipophilicity can be expressed in the so-called HLBvalue. According to a particularly preferred embodiment, the sucrosefatty acid mono-ester has an HLB-value of 8-18, more preferably of 11-17and most preferably of 13-16.

In a preferred embodiment, the fatty acid residue of the sucrose fattyacid mono-ester, is selected from C₈-C₁₈ fatty acids. In an even morepreferred embodiment, the fatty acid residue of the sucrose fatty acidmono-ester is a saturated C₁₀-C₁₈ fatty acid. In an even more preferredembodiment, the fatty acid residue of the sucrose fatty acid mono-esteris selected from lauric, palmitic or stearic acid. In a most preferredembodiment, the sucrose fatty acid mono-ester is sucrose mono-laurate.

In a preferred embodiment of the invention, the granulate contains 5-15wt. % of CBD, 10-25 wt. % of sucrose fatty acid mono-ester, 60-78 wt. %of lactose and 0-8 wt. % of other granulate excipients.

In a preferred embodiment of the invention, the ratio of CBD to sucrosefatty acid mono-ester in the granulate is within the range of 1:4-1:1,more preferably 1:3-1:1.5.

In a preferred embodiment of the invention, the lactose that is combinedwith the granulate and optional other tablet excipients to form thecompressed tablet, is anhydrous lactose (β-lactose) or α-lactosemonohydrate, most preferably it is α-lactose monohydrate. In a preferredembodiment, 70-100 wt. % of the lactose within the granulate consists ofα-lactose monohydrate, more preferably 75-100 wt. %, even morepreferably 80-100 wt. %. In a preferred embodiment, 90-100 wt. % of thelactose consists of crystalline lactose, more preferably 95-100 wt. %,even more preferably 98-100 wt. %. In a preferred embodiment, thelactose within the granulate is a spray-dried lactose. Preferably thelactose used for producing the granulate is obtainable by spray-drying asuspension of fine milled α-lactose monohydrate crystals in a solutionof lactose.

Commercially available sucrose fatty acid mono-esters usually containsmall amounts of sucrose fatty acid di-esters. The present granulatepreferably comprises less than 50 wt. % of sucrose fatty acid di-esterby weight of the sucrose fatty acid mono-ester, more preferably lessthan 10 wt. % of sucrose di-esters by weight of the sucrose fatty acidmono-ester.

The compressed tablet according to the invention may in addition to thegranulate and the lactose further optionally includes up to 30 wt. % ofother tablet excipients. These further tablet excipients areadvantageously chosen from the group consisting of coloring agents,flavoring or taste masking agents, muco-adhesive agents, diluents,binders, lubricants, additional disintegrants other than lactose,stabilizers, surfactants, glidants, plasticizers, preservatives andsweeteners. These tablet excipients may be distributed throughout thetablet or they may be contained in, for instance, an external coating,such as an enteric coating.

Suitable muco-adhesive agents that can be added to the compressedtablets are chosen from the group consisting of carbomers, cellulosederivatives, plant lectin, dextrin, hypromellose, chitosan, polyethyleneoxide, alginate and combinations thereof. In a preferred embodiment thecompressed tablets comprise 0-3 wt. % of muco-adhesive agents.

The additional disintegrants are advantageously chosen from the groupconsisting of crospovidone, croscarmellose sodium, sodium starchglycolate, hydroxypropyl cellulose, polacrilin potassium, pregelatinizedstarch, microcrystalline cellulose and combinations thereof. In apreferred embodiment the compressed tablets comprise up to 20 wt. % ofadditional disintegrants.

The compressed tablets of the present invention may suitably compriseone or more coatings layers. These layers together represent no morethan 20 wt. % of the tablet.

In order to enable easy removal of the compressed tablets from themoulds, the compressed tablets typically contains 0.1-10 wt. % of alubricant or gliding agent. Preferably, the lubricant or gliding agentis selected from the group consisting of talc, sodium stearyl fumarate,magnesium stearate, calcium stearate, hydrogenated castor oil,hydrogenated soybean oil, polyethylene glycol, starches, anhydrouscolloidal silica and combinations thereof. In a preferred embodiment thecompressed tablets comprise 0.5-2 wt. % of lubricant.

According to a preferred embodiment, the compressed tablets of thepresent invention comprise a combination of silica and lubricant.

Advantageously, the compressed tablets exhibit a certain level ofporosity in order to allow easy water access. Typically, the compressedtablets of the present invention exhibit a porosity of 1-50%, preferablyof 2-15%, said porosity being defined as the volume of void space in thecompressed tablets divided by the total volume of the compressedtablets, multiplied by 100. Analysis techniques for determining porosityof solid pharmaceutical dosage forms are known to those skilled in theart.

Another aspect of the invention relates to a method of manufacturing acompressed tablet as described herein before, said method comprising thesteps of:

-   -   providing a lactose powder having a mass weighted average        diameter of 32-250 μm, preferably of 45-250 μm;    -   combining the lactose powder with a granulation fluid to produce        a granulate, said granulation fluid comprising a solution of        CBD, sucrose fatty acid mono-ester and optionally further        granulate excipients in an organic solvent;    -   removing the organic solvent by evaporation to obtain the        granulate;    -   mixing the granulate with lactose and optionally further tablet        excipients to produce a tablet mixture; and    -   compressing the tablet mixture into a tablet.

In accordance with a preferred embodiment of the present method, thegranulation fluid is combined with the lactose powder by graduallyadding the granulation fluid to the lactose powder, whilst agitating thelactose powder. The granulation fluid may suitably be added onto apowder bed which is agitated under the influence of an impeller (e.g. ina high shear granulator, screws (e.g. in a twin screw granulator) or air(e.g. in a fluidized bed granulator). More preferably, the granulate isproduced in a high shear granulator.

As is known to those skilled in the art, the rate of adding thegranulation fluid to the powder, the ratio of granulation fluid topowder and the degree of agitation of the wet mass all affect the finalparticle size distribution of the granules. It is within the skills ofthe expert in the field of pharmaceutical drug formulation to steer atthe desired particle size distribution.

Preferably, the amount of granulation fluid employed in the preparationof the granulate is in the range of 5-100% by weight of the lactosepowder with which it is combined. Even more preferably, granulationfluid is employed in an amount of 10-50%, most preferably of 20-25% byweight of said lactose powder.

The granulation fluid is typically combined with the lactose powder at arate of at least 3 ml per kg of lactose powder per minute. Even morepreferably the addition rate is in the range of 4-250 ml/kg/min, mostpreferably in the range of 5-150 ml/kg/min.

In a preferred embodiment, the temperature of the granulation fluid isbetween 15° C. and 50° C. when it is combined with the lactose powder.

The organic solvent contained in the granulation fluid is preferablyC₁-C₃ alcohol, more preferably a C₁-C₃ alcohol chosen from the groupconsisting of methanol, ethanol, n-propanol, isopropyl alcohol andcombinations thereof. In a particularly preferred embodiment, the C₁-C₃alcohol is ethanol.

Evaporation of the organic solvent can be accomplished by any meansknown in the art. In a preferred embodiment, vacuum drying is applied toremove the organic solvent. In a more preferred embodiment, the vacuumdrying is applied at a temperature of between 20° C. and 70° C., evenmore preferably at a temperature of between 35° C. and 55° C.

In another preferred embodiment, the granulation fluid is prepared bycombining the CBD, sugar fatty acid mono ester and optionally furthergranulate excipients, in the (relative) amounts recited here above, inan organic solvent at a combined total level within the range of 0.3-1.9g per ml of solvent, more preferably within the range of 0.5-1.5 g perml of solvent, most preferably within the range of 0.7-1.4 g per ml ofsolvent.

In a preferred embodiment of the invention, the granulation fluidcomprises a dispersion or solution in the organic solvent of:

-   -   0.1-0.5 g/ml of CBD;    -   0.2-1 g/ml of sugar fatty acid mono-ester; and    -   0-0.4 g/ml of other granulate excipients;        preferably at a combined total level within the range of 0.3-1.9        g per ml of solvent, more preferably within the range of 0.5-1.5        g per ml of solvent, most preferably within the range of 0.7-1.4        g per ml of solvent.

In a preferred embodiment of the invention, the ratio of CBD to sucrosefatty acid mono-ester (w/w) in the granulation fluid is within the rangeof 1:4-1:1, more preferably 1:3-1:1.5.

The compressed tablets of the present inventions are convenientlyproduced in a tabletting machine. Tablet manufacturing methods by powdercompression are generally known to those skilled in the art.

Another aspect of the invention relates to compressed tablets comprisingCBD as defined herein for use in the treatment of psychosis disorders oranxiety disorders, said treatment comprising peroral administration ofone or more the compressed tablets in an amount that is equivalent to10-200 mg of CBD.

CBD-containing compressed tablets according to the invention areparticularly suitable for use in the treatment of a psychosis disorderselected from schizophrenia, schizophreniform disorder, schizoaffectivedisorder, brief psychotic disorder, delusional disorder, sharedpsychotic disorder, paraphenia. According to a particularly preferredembodiment, the tablets are used in the treatment of a psychosisdisorder selected from schizophrenia, schizophreniform disorder,schizoaffective disorder, paraphenia.

According to another preferred embodiment, the compressed tabletsaccording to the present invention are used in the treatment of ananxiety disorder selected from phobic disorder, generalized anxietydisorder, post-traumatic stress disorder, panic disorder,obsessive-compulsive disorder, agoraphobia. According to a particularlypreferred embodiment, the tablets are used in the treatment of ananxiety disorder selected from phobic disorder, generalized anxietydisorder, post-traumatic stress disorder.

In a preferred embodiment said treatment comprises peroraladministration of one or more of the compressed tablets in an amountthat is equivalent to 5-1000 mg of CBD, even more preferably in anamount that is equivalent to 10-750 mg and most preferably in an amountthat is equivalent to 15-500 mg of CBD.

According to another preferred embodiment, the treatment comprisesperoral administration of the compressed tablets in a daily amount thatis equivalent to 5-1000 mg of CBD, even more preferably in a dailyamount that is equivalent to 15-500 mg of CBD

In another preferred embodiment, said treatment comprises peroraladministration of 1 to 10 compressed tablets per day, more preferably 1to 5, even more preferably 1 to 3 tablets per day. The tablets areconveniently administered at regular time intervals in the range of 4-24hours, such as one tablet every 4 hours, every 6 hours, every 8 hours,or once a day.

Treatment of psychosis disorders or anxiety disorders in the context ofthe present invention involves both therapeutic and prophylactictreatments.

The compressed tablets of the present invention are advantageouslyemployed in the treatments of mammals, preferably of humans.

The following examples are meant to further illustrate the invention andsome of its preferred embodiments without intending to limit its scope.

EXAMPLES Example 1

A CBD-containing granulate was prepared via a wet-granulation method.The composition of the CBD-granulate is described in Table 1.

TABLE 1 composition of CBD-granulate Component wt. % CBD 8.0 Sucrosennonolaurate 16.0 Ascorbic acid 0.8 Lactose¹ 75.2 ¹spray-dried α-lactosemonohydrate, direct compression grade, mass weighted average diameterappr. 150 μm

A granulation fluid containing CBD, sucrose monolaurate (SML) andascorbic acid (AA) at a combined concentration of 1.2 g/ml was preparedas follows. The required amount of CBD was weighed in a beaker. Inanother beaker, the AA was dissolved in 165 ml of ethanol. The solutionwas heated to 60° C. and stirred to help the dissolution of AA.Dissolution of AA was completed in approximately 15 minutes. When the AAhad been dissolved, this solution was added to the beaker containing theCBD. The required amount of SML was also added to the beaker containingthe CBD. The mixture was heated to 45° C. and stirred to help thedissolution. This granulation fluid was stirred during 10 to 15 minutesuntil all the material had been dissolved.

The wet granulation process was performed as follows. Lactose wasweighed and transferred to the mixing bowl of a high shear granulator.The system was closed and the heating for the heating jacket of thegranulation vessel was turned on (set temperature of 40° C.). Beforeaddition of the granulating fluid, vacuum was applied and nitrogen waspumped into the vessel. Subsequently, the granulating fluid was added bydripping using a peristaltic pump with a flow of 9 ml/min while theimpeller and the chopper were turning. When the granulating fluid wascompletely added to the granulation vessel, the drying process started.Vacuum drying occurred under a stream of nitrogen (200 ml/min). Thedrying process was completed when the temperature (50° C.) and vacuumremained stable for at least 15 minutes and no liquid was coming fromthe condenser.

After completion of the drying process, the vacuum was released, thenitrogen flow was closed and the granulate was collected and transferredto a sieve. The granulate was sieved through sieves of 2.0 mm, 0.710 mmand 0.355 mm. The final granulate was packed into an aluminum bag. TheCBD-granulate had a mass weighted average diameter of 355 μm. Thebinding component of the granulate consisted of a solid dispersion ofCBD in SML.

Example 2

The CBD-granulate obtained in Example 1 was blended with excipients anddirectly compressed into tablets for peroral administration. Thecomponents used for tablet preparation are given in Table 2. Aspecification of the compressed tablets is given in Table 3.

TABLE 2 composition used for the preparation of a 340 mg tabletcomprising ~20 mg CBD Component wt. % Granulate 75 Lactose ¹ 23.8Magnesium stearate 1 Silicon dioxide, anhydrous 0.2 ¹ spray-driedα-lactose monohydrate, direct compression grade, mass weighted averagediameter appr. 150 μm

TABLE 3 specification of the compressed tablets Parameter MethodSpecification Hardness Ph. Eur. 2.9.8 ≥20 N Diameter — 10 mm THC contentHPLC ≤0.5% Dissolution Ph. Eur. 2.9.3 ≥75% (Q) within 45 minutesDisintegration Ph. Eur. 2.9.1 <15 minutes Residual ethanol Ph Eurr.2.4.24 ≤5000 ppm

Example 3

The rate of dissolution of CBD from the compressed tablets described inExample 2 was tested according to European Pharmacopeia (Ph. Eur. 2.9.3)for oral tablets. The rate of dissolution of pure CBD (20 mg) wasdetermined using the same method.

The dissolution medium consisted of a solution of 1 wt. % SDS in water.The pH of the medium had been adjusted to 7 with diluted HCl. During theexperiments, the temperature of the dissolution media was maintainedbetween 36 and 41° C. under stirring. After dropping the tablet in thedissolution medium, samples were taken at various time intervals with adisposable syringe. The samples were filtered immediately over a syringefilter into a HPLC vial and analyzed by HPLC. The results of thedissolution tests are summarized in Table 4

TABLE 4 % (w/w) of THC dissolved Time (in min.) Tablet CBD pure 1 2.82.6 4 21.5 9.2 8 45.0 18.6 15 65.4 27.4 30 70.3 35.2 45 69.1 42.4 6074.2 45.5

Example 4

Tablets from example 2 were packaged in aluminum pouches. These packagedtablets were stored under different storage conditions of 20° C.±5° C.and 40° C. for 1 year. The tablets were found to be stable under thesestorage conditions, i.e. CBD content after storage was still more than90% the original content.

Example 5

This example describes the production of a CBD-granulate in a Rotavapor.The composition of the granulate is described in table 5.

TABLE 5 Component wt. % CBD 6.7 Sucrose monolaurate 13.3 Ascorbic acid0.7 Lactose ¹ 79.4 ¹ spray-dried α-lactose monohydrate, directcompression grade, mass weighted average diameter appr. 150 μm

The granulation fluid was preparing dissolving the ascorbic acid (1.3 g)in 50 ml of ethanol and heating at 60° C. When the ascorbic acid wasdissolved the corresponding amount of sucrose monolaurate (26.6 g) andCBD (13.3 g) were added and the solution was stirred until all thematerial was dissolved.

The lactose (58.8 g) was introduced in a round bottom drying flask andpart of the granulation fluid was carefully poured on the lactose. Thematerial was mixed and dried at 40° C. The rest of the granulation fluidwas added and the mixing and drying was repeated until total solventevaporation.

Subsequently, additional lactose (100 g) and ethanol (appr. 60 g) wereadded and drying was continued at a temperature of 60° C. The finalgranulate was sieved through a 0.355 mm sieve.

Example 6

The CBD-granulate obtained in Example 5 was blended with excipients anddirectly compressed into tablets comprising 10 mg CBD for peroraladministration. The compressed tablets had an average weight of 200 mgand were composed of 75 wt. % of the CBD-granulate, 23.8 wt. % ofspray-dried α-lactose monohydrate, 1% of magnesium stearate and 0.2% ofsyloid. The tablets were packaged in aluminum pouches.

These tablets were submitted to a stability study during 1 year at −20°C., room temperature and 40° C., respectively. Tablets were found to bestable under all these storage conditions, i.e CBD content had decreasedby not more than 10% during the storage period.

Example 7

A CBD-granulate was produced as explained in example 1 but using asexcipient a mixture of 75 wt. % lactose and 25% microcrystallinecellulose. Compressed tablets were produced in the same way as describedin Example 2 and packaged in aluminum pouches.

These tablets were subjected to a stability study by keeping them for 6months at room temperature. The tablets described in Example 2 weresubjected to the same stability test.

After 6 months the CBD content of both types of tablets had decreased bynot more than 10%. After the 6 months of storage the level of impuritiesfound in the tablets produced with the blend of lactose andmicrocrystalline celloluse was twice as high as in the tablets ofExample 2.

Example 8

Oral tablets containing 11 mg CBD as described in example 6 and asoft-gel capsule containing 200 mg of pure CBD (powder) were used in apharmacokinetic study. Following ingestion of the capsule or 18 of theaforementioned tablets by a healthy volunteer, resulting in a dose of200 mg CBD in both cases, plasma concentrations of CBD were analyzedusing LC/MS/MS.

Peak plasma concentration (C_(max)), time to peak plasma concentration(t_(max)) and area under the curve from t=0 to infinity (AUC_((0,∞)))were calculated. The results are summarized in Table 6.

TABLE 6 Pharmacokinetic parameters Capsule Tablets C_(max) (ng ml⁻¹) 2.0112.7 t_(max) (min) 150 120 AUC_((0, ∞)) (ng ml⁻¹ min) 1.2 121.2

The invention claimed is:
 1. A compressed tablet having a tablet weightof 60-1200 mg and comprising: (a) 50-95 wt. % of a granulate; (b) 5-50wt. % of lactose; and (c) 0-30 wt. % of other tablet excipients; whereinthe granulate comprises: (i) 2-15 wt. % of cannabidiol; (ii) 2-30 wt. %of sucrose fatty acid mono-ester; (iii) 30-96 wt. % of lactose; and (iv)0-25 wt. % of other granulate excipients, wherein the granulate iscomposed of granules comprising lactose particles that are held togetherby a solid dispersion comprising cannabidiol and sucrose fatty acidmono-ester and optionally other granulate excipients; and wherein thecompressed tablet is obtained by: (a) providing a lactose powder; (b)combining the lactose powder with a granulation fluid comprising asolution of cannabidiol, sucrose fatty acid mono-ester and optionallyother granulate excipients in an organic solvent; (c) removing theorganic solvent by evaporation to produce a granulate; (d) mixing thegranulate with lactose and optionally other tablet excipients to producea tablet mixture; and (e) compressing the tablet mixture into a tablet.2. The compressed tablet according to claim 1, wherein the tabletcomprises 2-100 mg cannabidiol.
 3. The compressed tablet according toclaim 1, wherein the granulate is composed of granules comprisinglactose particles that are held together by a solid dispersioncomprising cannabidiol, antioxidant and sucrose fatty acid mono-esterand optionally other granulate excipients.
 4. The compressed tabletaccording to claim 3, wherein the granulate is composed of granulescomprising lactose particles that are held together by a soliddispersion, wherein the solid dispersion contains a dispersed phasecomprising cannabidiol, said dispersed phase having a volume weightedaverage diameter between 2 nm and 1 μm.
 5. The compressed tabletaccording to claim 1, wherein the lactose is anhydrous lactose orlactose monohydrate.
 6. The compressed tablet according to claim 1,wherein granules comprised in the granulate have a mass weighted averagediameter of 50-1000 μm.
 7. The compressed tablet according to claim 1,wherein the granulate comprises 0.2-1.5 wt. % of antioxidant.
 8. Thecompressed tablet according to claim 1, wherein the sucrose fatty acidmono-ester comprises saturated C₁₀-C₁₈ fatty acids.
 9. The compressedtablet according to claim 1, comprising 0-5% of Δ9-tetrahydrocannabinolby weight of cannabidiol.
 10. The compressed tablet according to claim1, wherein the lactose powder has a mass weighted average diameter of32-250 μm.
 11. The compressed tablet according to claim 1, wherein thegranulation fluid comprises an anti-oxidant.
 12. A method of treatingpsychosis disorders or anxiety disorders, comprising perorallyadministering one or more compressed tablets according to claim 1 in anamount that is equivalent to 5-1000 mg of cannabidiol.
 13. The methodaccording to claim 12, wherein the psychosis disorder is selected fromschizophrenia, schizophreniform disorder, schizoaffective disorder,and/or paraphenia.
 14. The method according to claim 12, wherein theanxiety disorder is selected from phobic disorder, generalized anxietydisorder, and/or post-traumatic stress disorder.